Ezonexa

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ESONEXA® (ESONEXA)

Composition:

Active substance: esomeprazole;

1 tablet contains 21.75 mg of esomeprazole magnesium dihydrate equivalent to 20 mg of esomeprazole, or 43.5 mg of esomeprazole magnesium dihydrate equivalent to 40 mg of esomeprazole;

Excipients: methacrylic acid copolymer dispersion, talc, triethyl citrate, hypromellose, spherical sugar, magnesium stearate, hydroxypropylcellulose, glycerol monostearate, polysorbate 80, microcrystalline cellulose, povidone, macrogol 6000, crospovidone, sodium stearyl fumarate; for the 20 mg dosage: Opadry Pink 03B34284 (hypromellose, titanium dioxide (E171), polyethylene glycol 400, iron oxide red (E172), iron oxide yellow (E172)); for the 40 mg dosage: Opadry Pink 03B34285 (hypromellose, titanium dioxide (E171), polyethylene glycol 400, iron oxide red (E172), iron oxide yellow (E172)).

Pharmaceutical form. Enteric-coated tablets.

Main physicochemical properties:

20 mg tablets: light pink, biconvex, elliptical, film-coated tablets, size (6.55 ± 0.4) mm × (13.6 ± 0.6) mm;

40 mg tablets: pink, biconvex, elliptical, film-coated tablets, size (8.2 ± 0.5) mm × (17 ± 0.6) mm.

Pharmacotherapeutic group.

Agents for treatment of peptic ulcer and gastroesophageal reflux disease. Proton pump inhibitors. ATC code A02BC05.

Pharmacological Properties

Pharmacodynamics

Esomeprazole is the S-isomer of omeprazole, which reduces gastric acid secretion through a specific mechanism of action. It is a specific inhibitor of the proton pump (PPI) in the parietal cell. The R- and S-isomers of omeprazole have equivalent pharmacodynamic activity.

Esomeprazole is a weak base that accumulates and is converted into its active form in the highly acidic environment of the secretory canaliculi of the parietal cell, where it inhibits the H⁺K⁺-ATPase enzyme—the proton pump—and thereby suppresses both basal and stimulated acid secretion.

Pharmacodynamic Effects

After oral administration of 20 mg and 40 mg esomeprazole, the effect begins within one hour. After repeated administration of 20 mg esomeprazole once daily for 5 days, the mean peak acid output following pentagastrin stimulation is reduced by 90% when measured 6–7 hours after dosing on day 5.

After 5 days of treatment with 20 mg and 40 mg esomeprazole orally, gastric pH remained above 4 for an average of 13 hours and 17 hours, respectively, and for more than 24 hours in patients with symptomatic reflux esophagitis. The proportion of patients with gastric pH above 4 for 8, 12, and 16 hours after administration of 20 mg esomeprazole was 76%, 54%, and 24%, respectively. Corresponding proportions for 40 mg esomeprazole were 97%, 92%, and 56%.

Using the area under the plasma concentration-time curve (AUC) as an indirect measure of systemic exposure, a relationship between acid suppression and drug exposure has been demonstrated.

Treatment of reflux esophagitis with esomeprazole 40 mg was successful in approximately 70% of patients after 4 weeks of treatment and in 93% after 8 weeks of treatment.

Administration of esomeprazole 20 mg twice daily for one week in combination with appropriate antibiotics resulted in successful eradication of Helicobacter pylori in approximately 90% of patients. After this one-week treatment, no further monotherapy with acid-suppressive agents was required for successful healing and symptom relief of uncomplicated duodenal ulcer.

In a randomized, double-blind, placebo-controlled clinical trial in patients with endoscopically confirmed peptic ulcer bleeding of Forrest class Ia, Ib, IIa, or IIb (9%, 43%, 38%, and 10%, respectively), patients were randomized to receive either esomeprazole, infusion solution (n = 375), or placebo (n = 389). After endoscopic hemostasis, patients received either intravenous esomeprazole 80 mg as a 30-minute infusion followed by continuous infusion at 8 mg/hour or placebo for 72 hours. After the initial 72-hour period, all patients received open-label oral esomeprazole 40 mg daily for 27 days to maintain acid suppression. The rebleeding rate within 3 days was 5.9% in the esomeprazole group and 10.3% in the placebo group. At 30 days after therapy, the rebleeding rates in the esomeprazole and placebo groups were 7.7% and 13.6%, respectively.

During treatment with acid-suppressing agents, serum gastrin levels increase in response to reduced acid secretion. Chromogranin A (CgA) levels also increase due to reduced gastric juice acidity. Because of elevated CgA levels, test results for neuroendocrine tumors may be affected. According to published data, PPIs should be discontinued at least 5–14 days before measuring CgA levels to allow CgA, which may be falsely elevated during PPI treatment, to return to normal ranges.

During long-term esomeprazole therapy, both in children and adults, an increase in the number of enterochromaffin-like cells (ECL cells) has been observed, possibly due to elevated serum gastrin levels. These findings are considered clinically insignificant.

During long-term treatment with acid-suppressing agents, a slight increase in the incidence of gastric glandular cysts has been observed. These changes are a physiological consequence of pronounced suppression of gastric juice secretion, are benign in nature, and resolve after discontinuation of therapy.

Reduced gastric juice secretion due to any PPI increases the number of bacteria normally present in the gastrointestinal tract. PPI treatment may increase the risk of gastrointestinal infections caused, for example, by Salmonella or Campylobacter, and possibly also Clostridium difficile in hospitalized patients.

Clinical Efficacy

Esomeprazole was more effective than ranitidine in the treatment of gastric ulcers in patients receiving nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors.

Esomeprazole was effective in preventing gastric and duodenal ulcers in patients receiving NSAIDs (in patients aged 60 years and/or with a history of ulcer), including those receiving COX-2 selective NSAIDs.

Children

In a study involving children with gastroesophageal reflux disease (GERD) (aged <1 to 17 years) receiving long-term PPI therapy, ECL cell hyperplasia of mild degree was observed in 61% of children, the clinical significance of which was unknown; no cases of atrophic gastritis or carcinoid tumors were reported.

Pharmacokinetics

Esomeprazole is acid-labile and administered orally as granules with an enteric coating. In vivo conversion to the R-isomer is negligible. Absorption of esomeprazole is rapid, with peak plasma concentration (C_max) reached approximately 1–2 hours after dosing. Absolute bioavailability is 64% after a single 40 mg dose and increases to 89% after repeated once-daily administration. For the 20 mg dose, corresponding values are 50% and 68%. The volume of distribution at steady state in healthy volunteers is 0.22 L/kg body weight. Esomeprazole is 97% bound to plasma proteins.

Food intake slows and reduces esomeprazole absorption, but this does not affect the action of esomeprazole on gastric acidity.

Metabolism and Elimination

Esomeprazole is completely metabolized via the cytochrome P450 (CYP) system. The major part of esomeprazole metabolism depends on the polymorphic CYP2C19, responsible for the formation of hydroxy- and desmethyl metabolites of esomeprazole, while the remainder is metabolized by the specific isoenzyme CYP3A4, which forms esomeprazole sulfone—the main metabolite in plasma.

The parameters below primarily reflect pharmacokinetics in patients with functional CYP2C19 enzyme (extensive metabolizers).

Total plasma clearance is approximately 17 L/h after a single dose and about 9 L/h after repeated administration. The plasma elimination half-life is approximately 1.3 hours after repeated once-daily dosing. The pharmacokinetics of esomeprazole have been studied at doses up to 40 mg twice daily. AUC increases with repeated administration. This increase is dose-dependent and results in more than dose-proportional increases in AUC after repeated dosing. This time- and dose-dependency is explained by reduced first-pass metabolism and systemic clearance due to inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulfone metabolite. Esomeprazole is completely cleared from plasma between doses, with no tendency for accumulation when administered once daily.

The main metabolites of esomeprazole do not affect gastric juice secretion. Approximately 80% of an oral dose of esomeprazole is excreted in urine as metabolites, and the remainder in feces. Less than 1% of the parent drug is found in urine.

Special Patient Populations

Poor Metabolizers

Approximately 2.9 ± 1.5% of the patient population has deficiency of the CYP2C19 enzyme (referred to as poor metabolizers). In these patients, esomeprazole metabolism is primarily mediated by CYP3A4. After repeated once-daily administration of 40 mg esomeprazole, the mean AUC in poor metabolizers is approximately 100% higher than in individuals with normal CYP2C19 function (extensive metabolizers). The mean peak plasma concentration is increased by approximately 60%. These findings have no impact on esomeprazole dosing.

Gender

After administration of a single 40 mg dose of esomeprazole, the mean AUC in women is 30% higher than in men. No gender-related differences were observed after repeated once-daily administration. These findings do not affect esomeprazole dosing.

Patients with Hepatic or Renal Impairment

Esomeprazole metabolism may be impaired in patients with mild to moderate hepatic dysfunction. Metabolism is reduced in patients with severe hepatic impairment, resulting in a doubling of AUC. Therefore, the maximum dose in patients with severe hepatic impairment should not exceed 20 mg. Esomeprazole and its metabolites do not tend to accumulate with once-daily administration.

Studies in patients with renal impairment have not been conducted. Since the kidneys are responsible for excretion of esomeprazole metabolites, not the parent compound, changes in metabolism are not expected in patients with renal impairment.

Elderly Patients

Esomeprazole metabolism is only slightly altered in elderly patients (71–80 years).

Use in Pediatrics

Children aged 12–18 years: after multiple doses of 20 mg and 40 mg esomeprazole, overall exposure and time to peak plasma concentration were similar to those in adults.

Clinical characteristics.

Indications.

Adults

Gastroesophageal reflux disease (GERD):

• treatment of erosive reflux esophagitis;
• long-term treatment of patients with healed esophagitis to prevent relapse;
• symptomatic treatment of GERD.

In combination with appropriate antibacterial medicinal products for eradication of Helicobacter pylori:

• treatment of duodenal ulcer associated with Helicobacter pylori;
• prevention of recurrence of peptic ulcers in patients with ulcers associated with Helicobacter pylori.

Patients requiring long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs):

• healing of NSAID-induced gastric ulcers;
• prevention of gastric and duodenal ulcers induced by NSAIDs in patients at risk.

Long-term treatment following intravenous administration of the drug to prevent recurrence of bleeding from peptic ulcers.

Treatment of Zollinger–Ellison syndrome.

Children aged 12 years and older

Gastroesophageal reflux disease (GERD):

• treatment of erosive reflux esophagitis;
• long-term treatment of patients with healed esophagitis to prevent relapse;
• symptomatic treatment of gastroesophageal reflux disease.

In combination with antibiotics for treatment of duodenal ulcer associated with Helicobacter pylori.

Contraindications.

Known hypersensitivity to esomeprazole, substituted benzimidazoles, or to any of the components of the medicinal product.

The drug, like other proton pump inhibitors, should not be used concomitantly with nelfinavir (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Effect of esomeprazole on the pharmacokinetics of other medicinal products

Protease inhibitors

Interactions between omeprazole and certain protease inhibitors have been reported, although the clinical significance and mechanism are not always fully understood. Increased gastric pH during treatment with the drug may alter the absorption of protease inhibitors. Another possible mechanism of interaction involves inhibition of CYP2C19 activity.

When co-administered with omeprazole, serum concentrations of atazanavir and nelfinavir were reduced; therefore, their concomitant use is not recommended. In healthy volunteers, co-administration of omeprazole (40 mg once daily) with atazanavir 300 mg/ritonavir 100 mg significantly reduced atazanavir exposure (AUC, Cmax, and minimum concentration [Cmin] decreased by approximately 75%). Increasing the atazanavir dose to 400 mg did not compensate for the effect of omeprazole on atazanavir exposure. When omeprazole (20 mg daily) was co-administered with atazanavir 400 mg/ritonavir 100 mg in healthy volunteers, atazanavir exposure decreased by approximately 30% compared to daily administration of 300 mg atazanavir/100 mg ritonavir without omeprazole 20 mg daily. Concomitant administration of omeprazole (40 mg daily) reduced mean AUC, Cmax, and Cmin of nelfinavir by 36–39%, and mean AUC, Cmax, and Cmin of its pharmacologically active metabolite M8 decreased by 75–92%. Due to the similarity in pharmacodynamic effects and pharmacokinetic properties between omeprazole and esomeprazole, esomeprazole should not be used concomitantly with atazanavir (see section "Special precautions for use"); concomitant use of esomeprazole with nelfinavir is contraindicated (see section "Contraindications").

In cases of concomitant therapy with omeprazole (40 mg daily), increased serum levels of saquinavir (in combination with ritonavir) have been reported (80–100% increase). Omeprazole treatment at a dose of 20 mg daily did not affect darunavir (with ritonavir) or amprenavir (with ritonavir) exposure. Treatment with esomeprazole at a dose of 20 mg daily did not affect amprenavir exposure (with or without ritonavir). Omeprazole treatment at a dose of 40 mg daily did not affect lopinavir exposure (with ritonavir).

Methotrexate

Elevated methotrexate levels have been observed in some patients when used concomitantly with PPIs.

When high-dose methotrexate is prescribed, temporary discontinuation of esomeprazole should be considered.

Tacrolimus

Increased serum levels of tacrolimus have been reported with concomitant use of esomeprazole. Close monitoring of serum tacrolimus concentrations and renal function (creatinine clearance) is recommended, with dose adjustment of tacrolimus if necessary.

Medicinal products whose absorption is pH-dependent

Suppression of gastric acid secretion during treatment with PPIs, including esomeprazole, may affect the absorption of medicinal products whose absorption is pH-dependent. As with other agents that reduce intragastric acidity, absorption of drugs such as ketoconazole, itraconazole, and erlotinib may be reduced, whereas absorption of digoxin may be increased during esomeprazole treatment. Concomitant administration of omeprazole (20 mg daily) and digoxin in healthy volunteers increased digoxin bioavailability by 10% (up to 30% in two out of ten subjects). Cases of digoxin toxicity have been rarely reported. However, caution should be exercised when prescribing high doses of esomeprazole to elderly patients. Enhanced therapeutic monitoring of digoxin is required.

Medicinal products metabolized by CYP2C9

Esomeprazole is an inhibitor of CYP2C19, the main enzyme responsible for esomeprazole metabolism. Therefore, when esomeprazole is combined with drugs metabolized by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, and phenytoin, plasma concentrations of these drugs may increase, potentially requiring dose reduction. This should be particularly considered when esomeprazole is prescribed on an "as-needed" basis.

Diazepam

Concomitant administration of diazepam and esomeprazole 30 mg resulted in a 45% reduction in diazepam clearance, a CYP2C19 substrate.

Phenytoin

An increase in plasma Cmin of phenytoin by 13% was observed in epileptic patients receiving concomitant phenytoin and esomeprazole 40 mg. Monitoring of plasma phenytoin levels at the initiation and discontinuation of esomeprazole therapy is recommended.

Voriconazole

Concomitant administration of omeprazole (40 mg once daily) increased Cmax and AUCτ of voriconazole (a CYP2C19 substrate) by 15% and 41%, respectively.

Cilostazol

Omeprazole, as well as esomeprazole, acts as an inhibitor of CYP2C19. In a cross-over study administering omeprazole 40 mg and cilostazol to healthy volunteers, Cmax and AUC of cilostazol increased by 18% and 26%, respectively, and one of its active metabolites increased by 29% and 69%, respectively.

Cisapride

In healthy volunteers, co-administration with esomeprazole (40 mg) increased AUC of cisapride by 32% and its elimination half-life (t½) by 31%, although no significant increase in maximum plasma concentration of cisapride was observed. No significant prolongation of the QTc interval, which was observed during cisapride monotherapy, was noted when cisapride was co-administered with esomeprazole (see also section "Special precautions for use").

Warfarin

A clinical study showed that co-administration of esomeprazole 40 mg in patients on warfarin therapy maintained coagulation time within acceptable limits. However, during the post-marketing period, several isolated cases of clinically significant increases in the international normalized ratio (INR) were reported during concomitant use of these medicinal products. Monitoring is recommended at the beginning and after discontinuation of combined therapy with esomeprazole and warfarin or other coumarin derivatives.

Clopidogrel

Pharmacokinetic (PK)/pharmacodynamic (PD) interaction data between clopidogrel (loading dose 300 mg/maintenance dose 75 mg daily) and esomeprazole (oral 40 mg daily), obtained in studies involving healthy volunteers, showed a mean 40% reduction in exposure to the active metabolite of clopidogrel and a mean 14% reduction in maximum inhibition of (ADP-induced) platelet aggregation.

In a study involving healthy volunteers evaluating the concomitant administration of clopidogrel with esomeprazole and acetylsalicylic acid (ASA) in fixed combination doses (20 mg + 81 mg, respectively) compared to clopidogrel monotherapy, exposure to the active metabolite of clopidogrel was reduced by nearly 40%.

However, the maximum level of inhibition of (ADP-induced) platelet aggregation was similar in the clopidogrel monotherapy group and the group receiving clopidogrel with esomeprazole and ASA.

Observational and clinical studies have yielded conflicting data on the clinical implications of PK/PD interactions between esomeprazole and major cardiovascular events. As a precautionary measure, concomitant use of esomeprazole and clopidogrel should be avoided.

Investigated medicinal products without clinically significant interaction

Amoxicillin and quinidine

Esomeprazole had no clinically significant effect on the pharmacokinetics of amoxicillin or quinidine.

Naproxen or rofecoxib

No pharmacokinetic interaction was observed during short-term studies of concomitant administration of esomeprazole with naproxen or rofecoxib.

Effect of other medicinal products on the pharmacokinetics of esomeprazole

Medicinal products that inhibit CYP2C19 and/or CYP3A4 activity

Esomeprazole is metabolized by CYP2C19 and CYP3A4 enzymes. Concomitant administration of esomeprazole and clarithromycin, a CYP3A4 inhibitor (500 mg twice daily), doubles the AUC of esomeprazole. Concomitant use of esomeprazole with a combined inhibitor of CYP2C19 and CYP3A4 may lead to more than a two-fold increase in esomeprazole exposure. The CYP2C19 and CYP3A4 inhibitor voriconazole increased AUCτ of omeprazole by 280%. Dose adjustment of esomeprazole is generally not required, except in patients with severe hepatic impairment or when long-term therapy is indicated.

Medicinal products that induce CYP2C19 and/or CYP3A4 activity

Drugs that induce CYP2C19 or CYP3A4 activity, or both enzymes (such as rifampicin and St. John's wort), may lead to decreased serum levels of esomeprazole by accelerating its metabolism.

Pediatric population

Drug interaction studies have been conducted only in adults.

Special precautions for use.

In the presence of alarm symptoms (e.g., significant unintentional weight loss, recurrent vomiting, dysphagia, hematemesis, or melena) and in cases where gastric ulcer is suspected or present, malignancy must be ruled out, as the use of the medicinal product Esoneksa® may mask symptoms and delay the establishment of an accurate diagnosis.

Patients who are taking the drug for a prolonged period (especially those receiving it for more than one year) should be under regular medical supervision.

Patients using the drug on an "as needed" basis should inform their physician if there is a change in the nature of their symptoms.

When prescribing esomeprazole for Helicobacter pylori eradication, potential drug interactions of all components of triple therapy must be considered. Clarithromycin is a potent inhibitor of CYP3A4; therefore, its contraindications and interactions must be taken into account (when triple therapy containing esomeprazole is used concomitantly with medicinal products metabolized by CYP3A4, such as cisapride).

The use of PPIs may slightly increase the risk of gastrointestinal infections, such as Salmonella and Campylobacter (see section "Pharmacodynamics").

Esomeprazole, like all drugs that inhibit hydrochloric acid secretion, may reduce absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with low vitamin B12 levels and in those at risk of reduced vitamin B12 absorption during long-term treatment.

Hypomagnesemia
Cases of severe hypomagnesemia have been reported in patients treated with PPIs, such as esomeprazole, for at least 3 months, and in most cases, for over 1 year. Severe manifestations of hypomagnesemia, such as tetany, delirium, seizures, dizziness, ventricular arrhythmias, and increased fatigue, may develop suddenly or insidiously. In most patients with hypomagnesemia, the condition was corrected by magnesium replacement therapy and discontinuation of PPI treatment.

For patients requiring long-term treatment or those receiving concomitant therapy with digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), physicians should monitor magnesium levels before initiating PPI therapy and periodically during treatment.

Risk of fractures

The use of PPIs, particularly at high doses and over a prolonged period (>1 year), may slightly increase the risk of fractures of the hip, wrist, and spine, primarily in elderly patients or those with other identified risk factors. Observational studies suggest that PPIs may increase the overall risk of fractures by 10–40%. This increased risk is often associated with other risk factors. Patients at risk of osteoporosis should receive treatment according to current clinical guidelines and should also take adequate amounts of vitamin D and calcium.

Subacute cutaneous lupus erythematosus (SCLE)

The use of PPIs has been associated with very rare cases of SCLE. If skin rashes, particularly on sun-exposed areas, and joint pain occur, the patient should seek immediate medical attention. The physician should consider discontinuing Esoneksa®. Previous occurrence of SCLE during PPI treatment significantly increases the risk of SCLE with subsequent treatment with other PPIs.

Combination with other medicinal products

Concomitant use of esomeprazole and atazanavir is not recommended (see section "Interaction with other medicinal products and other forms of interaction"). If combination of atazanavir with PPIs cannot be avoided, close monitoring of patients in an inpatient setting is recommended, along with increasing the atazanavir dose to 400 mg with 100 mg ritonavir; the esomeprazole dose should not exceed 20 mg.

Esomeprazole is an inhibitor of CYP2C19. Potential interactions with medicinal products metabolized by CYP2C19 must be considered before initiating or immediately after discontinuing esomeprazole. An interaction between clopidogrel and esomeprazole has been observed (see section "Interaction with other medicinal products and other forms of interaction"). The clinical significance of this interaction has not been definitively established. As a precautionary measure, concomitant use of esomeprazole and clopidogrel should be avoided.

When prescribing esomeprazole on an "as needed" basis, fluctuations in esomeprazole concentration due to interactions with other pharmaceutical products must be considered (see section "Interaction with other medicinal products and other forms of interaction").

Severe cutaneous adverse reactions

Very rarely, severe cutaneous adverse reactions have been reported with esomeprazole use, including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS), which may be life-threatening.

Patients should be informed about the symptoms of severe skin reactions (erythema multiforme/Stevens-Johnson syndrome/toxic epidermal necrolysis/DRESS) and the need to seek immediate medical attention if such symptoms occur.

Esomeprazole should be discontinued immediately if symptoms of severe skin reactions occur, and additional medical care and close monitoring should be provided as needed.

If a patient develops such a severe adverse reaction as erythema multiforme/Stevens-Johnson syndrome/toxic epidermal necrolysis/DRESS during esomeprazole treatment, reinitiating esomeprazole therapy is absolutely contraindicated.

Sucrose

This medicinal product contains sucrose. Patients with rare hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should not take this product.

Effect on laboratory test results

Elevated chromogranin A (CgA) levels may interfere with tests for detecting neuroendocrine tumors. To prevent this interference, esomeprazole treatment should be discontinued at least 5 days before CgA testing (see section "Pharmacodynamics"). If CgA and gastrin levels have not returned to the reference range after the first measurement, the test should be repeated 14 days after completion of PPI treatment.

Use during pregnancy or breastfeeding.

Pregnancy

Currently, there is insufficient data on the use of the drug during pregnancy. A somewhat larger amount of data on the use of the racemic mixture of omeprazole during pregnancy indicates no effect on congenital malformations or fetotoxicity. Animal studies with esomeprazole have not revealed any direct or indirect harmful effects on embryonic/fetal development. Studies in animals with the racemic mixture have not shown any direct or indirect effects on pregnancy, delivery, or postnatal development. The drug should be prescribed to pregnant women with caution.

A moderate amount of data from pregnant women (from 300 to 1000 pregnancy cases) indicates no malformative effects or toxic effects of esomeprazole on the fetus/neonatal health.

Results of animal studies indicate no direct or indirect harmful effects of the drug on reproductive function due to its toxic effects.

Breastfeeding period

It is unknown whether esomeprazole passes into human breast milk. There is insufficient information on the consequences of esomeprazole exposure in newborns/infants. Esomeprazole should not be used during breastfeeding.

Fertility

Results of animal studies with the racemic mixture of omeprazole indicate no effect of omeprazole on fertility with oral administration.

Ability to affect reaction speed when driving or operating machinery.

Esomeprazole has minimal effect on the ability to drive vehicles or operate machinery. Adverse reactions such as dizziness (uncommon) and blurred vision (rare) have been reported (see section "Adverse reactions"). If such disorders occur, patients should not drive vehicles or operate machinery.

Method of Administration and Dosage

Esonex tablets should be swallowed whole with an adequate amount of liquid. The tablets must not be chewed or crushed.

For patients who have difficulty swallowing, it is recommended to dissolve the tablet in 100 mL of non-carbonated water, stir until the tablet disintegrates, and immediately drink the microgranule suspension or within 30 minutes. Then fill the glass halfway with water, stir the remaining residue, and drink it. Other liquids must not be used, as they may damage the enteric coating. The microgranules must not be chewed or crushed.

For patients who have difficulty swallowing, the tablet may be administered via a nasogastric tube after dissolving it in half a glass of non-carbonated water. It is very important that the syringe and tube used for this procedure are appropriate.

Administration of the drug via nasogastric tube:

1. Place the tablet into a suitable syringe and fill it with approximately 25 mL of water and 5 mL of air. For certain tubes, 50 mL of water may be required to prevent obstruction of the tablet passage.
2. Shake the syringe for 2 minutes to allow the tablet to disintegrate.
3. Hold the syringe vertically with the tip facing upwards and check the patency of the tip.
4. Attach the syringe to the tube, holding it vertically.
5. Shake the syringe and turn it with the tip facing downwards. Quickly administer 5–10 mL of liquid. After administration, turn the syringe and shake it again (the syringe should be held vertically to prevent clogging the tip).
6. Turn the syringe again and administer another 5–10 mL of liquid into the tube. Repeat the procedure until the syringe is empty.
7. To rinse any remaining drug residue, fill the syringe with 25 mL of water and 5 mL of air, shake the syringe, turn it, and quickly administer the liquid. For certain tubes, 50 mL of water may be required.

Adults

Gastroesophageal reflux disease (GERD):

• Treatment of erosive reflux esophagitis: 40 mg once daily for 4 weeks. An additional 4 weeks of therapy are recommended for patients in whom esophagitis has not healed or symptoms persist.
• Long-term treatment of patients with healed esophagitis to prevent relapse: 20 mg once daily.
• Symptomatic treatment of GERD: 20 mg once daily for patients without esophagitis. If symptom control has not been achieved after 4 weeks of treatment, the patient should undergo further evaluation. After symptom resolution, continued control may be maintained with 20 mg once daily. For adults, an "on-demand" regimen may be used: 20 mg once daily as needed. For patients using NSAIDs who are at risk of developing gastric or duodenal ulcers, continued symptom control using an "on-demand" regimen is not recommended.

In combination with antibacterial agents for eradication of Helicobacter pylori, and also for:

• Treatment of duodenal ulcer caused by Helicobacter pylori, and
• Prevention of recurrence of peptic ulcers in patients with ulcers associated with Helicobacter pylori: 20 mg of Esonex drug combined with 1 g of amoxicillin and 500 mg of clarithromycin twice daily for 7 days.

Patients requiring long-term NSAID therapy:

• Treatment and prevention of ulcers caused by prolonged NSAID use: The recommended dose is 20 mg once daily for 4–8 weeks.
• Prevention of gastric and duodenal ulcers associated with NSAID therapy in high-risk patients: The recommended dose is 20 mg once daily.

Long-term treatment following intravenous administration of the drug for prevention of recurrent bleeding from peptic ulcers: 40 mg once daily for 4 weeks following intravenous administration of the drug for prevention of recurrent peptic ulcer bleeding.

Treatment of Zollinger–Ellison syndrome: 40 mg twice daily. Dosage should be individually adjusted according to clinical indications. Based on available clinical data, most patients achieve symptom control with doses ranging from 80 mg to 160 mg of esomeprazole per day. If the daily dose exceeds 80 mg, it should be divided into two administrations.

Special Patient Groups

Patients with Renal Impairment

Dose adjustment is not required in patients with renal impairment. Due to lack of experience with the use of Esonex in patients with severe renal insufficiency, the drug should be administered with caution in such patients (see section "Pharmacokinetics").

Hepatic Impairment

Dose adjustment is not required in patients with mild to moderate hepatic impairment. For patients with severe hepatic impairment, the maximum dose of Esonex should not exceed 20 mg (see section "Pharmacokinetics").

Elderly Patients

Dose adjustment is not required in elderly patients.

Pediatric Population

Children under 12 years of age

The drug should not be used in children under 12 years of age due to lack of data on efficacy and safety in this age group.

Children aged 12 years and older

Gastroesophageal reflux disease (GERD):

• Treatment of erosive reflux esophagitis: 40 mg once daily for 4 weeks; an additional 4 weeks of treatment is recommended for patients with unhealed esophagitis or persistent symptoms.
• Long-term treatment of patients with healed esophagitis to prevent relapse: 20 mg once daily.
• Symptomatic treatment of GERD: The dose for patients without esophagitis is 20 mg once daily. If symptom control has not been achieved after 4 weeks of treatment, the patient should undergo further evaluation. After symptom resolution, continued control may be achieved by administering the drug at a dose of 20 mg once daily.

Treatment of duodenal ulcer caused by Helicobacter pylori

When selecting appropriate combination therapy, official national, regional, and local guidelines regarding bacterial resistance, duration of treatment (usually 7 days, but sometimes up to 14 days), and proper use of antibacterial agents should be considered. Treatment should be conducted under the supervision of a specialist.

Dosing Recommendations

Body weight	Dosage
30–40 kg	In combination with two antibiotics: Esonex® 20 mg, amoxicillin 750 mg and clarithromycin 7.5 mg/kg body weight – all medications are taken simultaneously twice daily for one week.
> 40 kg	In combination with two antibiotics: Esonex® 20 mg, amoxicillin 1 g and clarithromycin 500 mg – all medications are taken simultaneously twice daily for one week.

Children

The drug should not be used in children under 12 years of age, as data on such use are lacking.

It may be used in children aged 12 years and older for the following indications:

Gastroesophageal reflux disease (GERD)

• Treatment of erosive reflux esophagitis;
• Long-term maintenance treatment of patients with healed esophagitis to prevent relapse;
• Symptomatic treatment of gastroesophageal reflux disease (GERD).

In combination with antibiotics for the treatment of duodenal ulcer associated with Helicobacter pylori.

Overdose.

Data regarding intentional overdose are limited. Gastrointestinal symptoms and weakness have been reported following ingestion of 280 mg of esomeprazole. A single dose of esomeprazole 80 mg is not associated with severe adverse effects. There is no known specific antidote.

Esomeprazole is highly bound to plasma proteins, therefore hemodialysis is not effective. Treatment should be symptomatic and supportive.

Adverse Reactions

Summary of safety profile

The most commonly observed adverse reactions during clinical trials (as well as in the post-marketing period) include headache, abdominal pain, diarrhea, and nausea. Furthermore, the safety profile of the medicinal product is consistent across different dosage forms, indications, age groups, and patient populations. Dose-dependent adverse reactions have not been identified.

List of adverse reactions

The adverse reactions listed below have been reported or suspected during clinical trials and in the post-marketing period of the medicinal product. None of these reactions were found to be dose-dependent.

Reactions are listed by frequency: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders

Rare: leukopenia, thrombocytopenia.

Very rare: agranulocytosis, pancytopenia.

Immune system disorders

Rare: hypersensitivity reactions such as fever, angioedema, and anaphylactic reaction/shock.

Metabolism and nutrition disorders

Uncommon: peripheral edema.

Rare: hyponatremia.

Frequency not known: hypomagnesemia (see section "Special precautions for use"), severe hypomagnesemia may correlate with hypocalcemia. Hypomagnesemia may also be associated with hypokalemia.

Psychiatric disorders

Uncommon: insomnia.

Rare: agitation, depression, confusion.

Very rare: aggression, hallucinations.

Nervous system disorders

Common: headache.

Uncommon: dizziness, paraesthesia, somnolence.

Rare: taste disturbance.

Eye disorders

Rare: blurred vision.

Ear and labyrinth disorders

Uncommon: vertigo.

Respiratory, thoracic and mediastinal disorders

Rare: bronchospasm.

Gastrointestinal disorders

Common: abdominal pain, constipation, diarrhea, bloating, nausea, vomiting, gastric fundic gland polyps (benign).

Uncommon: dry mouth.

Rare: stomatitis, gastrointestinal candidiasis.

Frequency not known: microscopic colitis.

Hepatobiliary disorders

Uncommon: increased liver enzymes.

Rare: hepatitis, with or without jaundice.

Very rare: hepatic reactions, including hepatic failure, encephalopathy in patients with liver disease.

Skin and subcutaneous tissue disorders

Uncommon: dermatitis, pruritus, urticaria, rash.

Rare: alopecia, photosensitivity.

Very rare: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

Frequency not known: subacute cutaneous lupus erythematosus (see section "Special precautions for use").

Musculoskeletal and connective tissue disorders

Uncommon: fractures of the hip, wrist, and spine (see section "Special precautions for use").

Rare: arthralgia, myalgia.

Very rare: muscle weakness.

Renal and urinary disorders

Very rare: interstitial nephritis; in some patients, renal failure has also been reported.

Reproductive system and breast disorders

Very rare: gynecomastia.

General disorders

Rare: malaise, increased sweating.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua/.

Shelf life. 2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions. Store in the original packaging at a temperature not exceeding 30 °C.

Keep out of reach of children.

Packaging.

Ezonexa® 40 mg: 7 tablets in blisters. 1, 2, or 4 blisters per carton (packaged from bulk supplied by the manufacturer Balkanpharma Dupnitsa AD, Bulgaria).

Ezonexa® 20 mg: 7 tablets in blisters. 2 or 4 blisters per carton (packaged from bulk supplied by the manufacturer Balkanpharma Dupnitsa AD, Bulgaria).

Prescription category. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address and place of business.

74 Kyrylivska Street, Kyiv, 04080, Ukraine.